Novel Agents Show Promise Against Endocrine-resistant Breast Cancer

Several novel agents, including checkpoint inhibitors, are being tested and may soon be approved for the treatment of metastatic breast cancer. Many appear, however, to come with significant side effects and high costs, according to Hope S. Rugo, MD, professor of medicine and the director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

Dr Rugo gave a talk on the latest approaches for treating endocrine resistance mechanisms of breast cancer at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting.1 While new therapies are improving response and response duration to hormone therapy in metastatic breast cancer, Dr Rugo explained that understanding toxicity and prospective management are critical.

Investigators have pinpointed a host of resistance mechanisms due to genetic and epigenetic alterations. They include acquired mutations that are now being targeted, including ER-alpha (ESR1), constitutive activation of cyclin-dependent kinases (CDK) 4 and 6, fibroblast growth factor receptor (FGFR) pathways, and epigenetic modifications by histone deacetylase (HDAC), as well as others.

Dr Rugo said PI3K is the most commonly altered pathway in hormone receptor–positive (HR+) breast cancer, and multiple agents that target this pathway are being studied. Unfortunately, there are currently no markers of PI3K pathway activation that have been identified to help single out which patients are most likely to benefit from this therapy.

“The most promising current targeted agents are being studied in the adjuvant and neoadjuvant settings,” said Dr Rugo. “There are 2 active agents that are in phase 3 trials that seem more active and tolerable. Alpelisib, an alpha-specific PI3K inhibitor, in the SOLAR 1 trial in combination with fulvestrant, taselisib, and alpha and delta PI3K inhibitor, in the SANDPIPER trial in combination with fulvestrant. Both agents have showed very encouraging data in the early phase setting, with somewhat different toxicity profiles.”

The mTOR inhibitor, everolimus, was the first targeted agent to obtain regulatory approval for treatment of hormone receptor positive, HER2-negative breast cancer. Everolimus blocks mTOR, which is downstream of PI3K and, in combination with exemestane following prior hormone therapy, doubled progression-free survival. “Use is somewhat limited by toxicity, in particular stomatitis. Recent data suggest that steroid mouthwash markedly reduces mTOR inhibitor associated stomatitis,” said Dr Rugo. “And, we discovered anecdotally that antihistamines can help to prevent the rashes associated with alpelisib. For palbociclib, dose delays and reductions are the most important management strategy. One of the most important tips is making sure both patients and staff are educated about management of toxicity.”

Ongoing trials are evaluating inhibitors of the PI3K pathway, CDK4/6, and HDAC, primarily in combination with hormone therapy in the metastatic, adjuvant, and neoadjuvant settings. Dr Rugo said combination therapy targeting 2 or more pathways is also under investigation.

“Two pan-PI3K inhibitors have been tested, pictilisib in the FERGI trial with fulvestrant, which showed no benefit over fulvestrant alone, and the phase 3 BELLE trial with buparlisib and fulvestrant, which showed no clinical significant benefit over fulvestrant alone, but had very interesting correlative studies looking at activated PI3K in circulating plasma DNA. The lack of significant efficacy and the toxicity profile, however, make buparlisib a poor candidate for further development,” Dr Rugo told Cancer Therapy Advisor.

Oncologist Martine Extermann, MD, PhD, a senior member of Senior Adult Oncology Program at the Moffitt Cancer Center in Tampa, Florida, said we are now moving toward a much more tailored approach in the treatment of breast cancer, with several novel combination therapies heading to the clinic. “There are more drugs that are being developed,” Dr Extermann told Cancer Therapy Advisor. “I think we have seen tremendous improvements in survival. Nowadays, for patients with metastatic disease, I tell a woman that this has become a chronic disease. Most of my patients are in now for the long haul. The 5-year survival rates over the past 5 years have almost doubled.”

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